Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors.
The structure-activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl) substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC(50)=1.3 microM) with good potency against the K103R mutant (EC(50)=4.8 microM). Docking simulations helped to rationalize the SARs.
Spallarossa
Andrea
A
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. andrea.spallarossa@unige.it
Cesarini
Sara
S
Ranise
Angelo
A
Bruno
Olga
O
Schenone
Silvia
S
La Colla
Paolo
P
Collu
Gabriella
G
Sanna
Giuseppina
G
Secci
Barbara
B
Loddo
Roberta
R
D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase